High levels of LDL cholesterol (LDL-c) and low levels of HDL cholesterol (HDL-c) are independent risk factors for coronary artery disease (CAD). The first aim of the mentored-phase of this application is to identify novel genes associated with HDL-c, LDL-c, and triglyceride levels by completing meta-analyses for genome-wide association scans in large stage 1 samples, together with follow-up in stage 2 samples. This approach has recently been successful in identifying seven novel gene regions associated with HDL-c, LDL- c or triglycerides at a genome-wide significant threshold. To further explore the seven novel gene regions as well as any novel genes identified in the first aim, the second aim proposes comprehensive re-sequencing of 1600 individuals for genes within the associated regions as well as association signals that do not contain a gene, which can be 100 kb from strong biological candidate genes. The goal of this approach is to uncover novel signatures of long-range regulatory elements that influence expression of distant genes, and this will be explored as the first aim during the independent phase of the award. The final aim during the mentored- phase of the award is to re-sequence targeted exonic and conserved regions near lipid-associated signals in individuals with extreme trait values to identify rare, disruptive single nucleotide polymorphisms or copy number variants. These disruptive changes may provide valuable clues about which gene in a potentially large region may be involved in lipid metabolism, a reversal of the typical paradigm to identify common variants in genes that contain rare disruptive mutations for related Mendelian disorders. The final aim for the independent phase of the award is to use information from the 1000 Genomes Project to impute and test ~10 million SNPs for association with lipid levels, catalog associated variants in associated regions and identify signatures of long-range regulatory elements. RELEVANCE (See Instructions): The identification of novel genes and functional elements associated with HDL-c, LDL-c and triglyceride levels is likely to have a significant impact on our understanding of the mechanisms of heart disease and has the potential to lead to new treatments.